Cardiovascular disease remains a major Public Health problem and is the leading cause of death in the US. The degree to which blood pressure (BP) changes in response to a dietary salt manipulation varies widely among humans. Many adults have a minimal change in BP despite large changes in dietary salt, which is termed salt-resistant BP. However, there may be pathophysiological consequences to a high salt diet in humans apart from the effect of salt on BP. Animal models support the conclusion that excess dietary salt contributes to endothelial abnormalities independent of BP. Dietary salt-induced increases in oxidative stress may be one of the factors impairing nitric oxide (NO) release. Based on the foregoing, our global hypothesis is that dietary salt intake will adversely affect vascular endothelial function independently of mean arterial BP in humans. We propose to investigate the effects of dietary salt on endothelial-dependent dilation of a conduit artery (i.e., brachial) and NO-mediated vasodilation of the cutaneous microvessels. We specifically hypothesize that high dietary salt will cause a decline in endothelial-dependent dilation and NO-mediated cutaneous vasodilation. We also hypothesize that oxidative stress will increase during the high dietary salt condition, and that the dietary salt-induced decline in cutaneous vasodilation will be attenuated by local ascorbic acid infusion providing functional evidence for a role of oxidative stress. Endothelial cells will be obtained to assess oxidant damage as well as oxidant and antioxidant enzyme content. These hypotheses will be tested in adults with salt-resistant BP. Young and middle-aged adults will undergo a 21-day controlled feeding study where they will consume a 1.3 g salt diet for 7 days, a 6 g salt diet for 7 days, and a 20 g salt diet for 7 days (crossover design, diet order sequence randomized;fixed potassium intake). Twenty-four hour ambulatory BP and urine collections during each diet condition will permit the individual assessment of salt sensitivity of BP. Flow mediated dilation of the brachial artery will be used to assess conduit endothelial- dependent dilation and cutaneous vasodilation in response to local heating using laser Doppler flowmetry and intradermal microdialysis will be assessed in the forearm to evaluate the microvasculature. Cutaneous vasodilation in response to local heating will be assessed at a Ringers (control) site, L-NAME site (to assess the NO contribution), and an ascorbic acid site (to assess the role of oxidative stress). These measures will be made during the last day of the 1.3g, 6 g, and 20g dietary salt conditions. The range of dietary salt intakes is purposely wide to allow the assessment of dose-response relationships in endothelial responses. This comprehensive endothelial assessment in humans during a controlled feeding study will allow us to determine if excess dietary salt is impairing endothelial-dependent vasodilation at both macro- and microvascular levels. PUBLIC HEALTH RELEVANCE: Dietary salt increases blood pressure in some, but not all adults. There is evidence in experimental animals that excess dietary salt may damage the blood vessels even if blood pressure does not rise. The purpose of this investigation is to determine if this also occurs in middle-aged adults with normal blood pressure.